Impaired motor-to-sensory transformation mediates auditory hallucinations

Distinguishing reality from hallucinations requires efficient monitoring of agency. It has been hypothesized that a copy of motor signals, termed efference copy (EC) or corollary discharge (CD), suppresses sensory responses to yield a sense of agency; impairment of the inhibitory function leads to hallucinations. However, how can the sole absence of inhibition yield positive symptoms of hallucinations? We hypothesize that selective impairments in functionally distinct signals of CD and EC during motor-to-sensory transformation cause the positive symptoms of hallucinations. In an electroencephalography (EEG) experiment with a delayed articulation paradigm in schizophrenic patients with (AVHs) and without auditory verbal hallucinations (non-AVHs), we found that preparing to speak without knowing the contents (general preparation) did not suppress auditory responses in both patient groups, suggesting the absent of inhibitory function of CD. Whereas, preparing to speak a syllable (specific preparation) enhanced the auditory responses to the prepared syllable in non-AVHs, whereas AVHs showed enhancement in responses to unprepared syllables, opposite to the observations in the normal population, suggesting that the enhancement function of EC is not precise in AVHs. A computational model with a virtual lesion of an inhibitory inter-neuron and disproportional sensitization of auditory cortices fitted the empirical data and further quantified the distinct impairments in motor-to-sensory transformation in AVHs. These results suggest that “broken” CD plus “noisy” EC causes erroneous monitoring of the imprecise generation of internal auditory representation and yields auditory hallucinations. Specific impairments in functional granularity of motor-to-sensory transformation mediate positivity symptoms of agency abnormality in mental disorders.


Introduction
Perceptual experiences can be induced by sensory processing [1,2] as well as constructed without external stimuli, such as memory retrieval [3] and mental imagery [4][5][6][7][8].Such distinct causes of perceptual experiences necessitate efficient monitoring to distinguish the inducing sources; failure of monitoring may result in hallucinations [9,10].For example, patients with auditory hallucinations, the core symptoms of schizophrenia, often 'hear' voices in the absence of sound [11].Patients may fail to distinguish between their thoughts [e.g., inner speech, 12] and externally generated voices, resulting in a reduced ability to recognize thoughts as self-generated [13,14].
That is, the symptoms of hallucinations have been attributed to the malfunction of self-monitoring [15,16].
Self-monitoring can be achieved with internal forward models [17,18], in which a copy of motor signals, termed corollary discharge (CD) [19] or efference copy (EC) [20], transmits to sensory regions (motor-to-sensory transformation) and suppresses sensory neural activities.The internal forward models have been evident ubiquitously across the animal kingdom [21] and the sensory suppression has been hypothesized as an index for signaling the impending reafference as the consequence of an agent's own actions --the sense of agency [22][23][24][25].That is, the suppression function of motor signals may provide an automatic computation to distinguish the sensory neural responses that are either internally induced or evoked by external stimulation [22,26].
Impairment of the inhibitory functions in motor-to-sensory transformation may result in a malfunction of self-monitoring and lead to auditory hallucinations [16,27,28].
However, how can the monitoring function of agency inhibit the sensory processing, while at the same time constructing the positive symptoms of auditory hallucinations?
Hallucinations are perceptual-like experiences that require specific neural representation activated without sensory stimulation [29].The sole inhibitory function of the motor copies cannot fully explain the symptoms of auditory hallucinations and is challenged by recent empirical findings.For example, action-induced enhancement has been found in a subset of sensory cortices in addition to action-induced suppression [30][31][32][33][34]. Auditory neural representations are constructed in auditory working memory based on covert speaking [8,35,36].This motor-based auditory working memory (i.e.inner speech) that activates specific neural representation may be misattributed to external sources because of the impaired self-monitoring function in schizophrenia [37,38].All these recent results hint that the copy of motor signals may have a function that sensitizes the sensory cortices in addition to the inhibitory function for monitoring agency.The combination of two complementary functions may mediate the positive symptoms of auditory hallucinations.
A recent study provided preliminary evidence supporting a hypothesis of distinct modulatory functions of motor signals on perceptual processes [39] --the CD function is generic motor discharge available throughout the course of action and can inhibit processes in the connected sensory regions for indicating all possible sensory consequences of actions [40] (Fig. 1A, cyan arrow).Whereas the EC function is a copy of a specific motor plan and selectively enhances the sensitivity to sensory reafference targets caused by actions (Fig. 1A, red arrow).Based on this theoretical framework, in this study, we hypothesize that selective impairments in CD and EC functions mediate the positive symptoms of auditory hallucinations.Specifically, the CD inhibitory function that should be available in the early stage of motor intention does not operate normally in all schizophrenia patients (Fig. 1B&C, grey arrows) --the negative symptoms (e.g.lack of desire) in patients without AVHs (non-AVHs) may have weaker movement intention and hence diminish CD signals at the beginning stage of speaking (Fig. 1B, only left part of CD arrow is grey); whereas in patients with AVHs, in addition to the negative symptoms, the deficit in the self-monitoring of agency is manifested in the impairment of the inhibitory function of CD throughout the entire course of action -a 'broken' CD (Fig. 1C, the entire CD arrow is grey).
When EC is available after specific movement plans have been formed, the enhancement function of EC on the prepared speech target is intact in non-AVHs patients (Fig. 1B, red arrow).Whereas, in patients with AVHs, the EC enhancement function is imprecise (Fig. 1C, hatched red arrow) and modulates both target reafference and its neighboring auditory units -a 'noisy' EC (potential causes of various perceptual-like auditory and verbal contents during hallucinations).That is, the positive symptoms of auditory hallucinations are mediated by the combination of a 'broken' CD and 'noisy' EC.This hypothesis of distinct impairments in motor-to-sensory transformation predicts that 1) the suppression effects of general speech preparation (e.g.preparing to speak without knowing what to say) that was observed in normal population would be absent in both patients with and without AVHs, and 2) non-AVHs patients would show identical enhancement effects of specific speech preparation (e.g.preparing to speak a given syllable) as in normal population, but the modulation effects of specific speech preparation would be different in patients with AVHs from those in non-AVHs and normal population.The function of CD is inhibiting all sensory regions that are connected with the activated motor system, indicating the impending sensory consequences of actions and hence yielding the sense of agency (Fig. 1A, cyan arrow).Efference copy (EC), a duplicate of the planned motor signals, is available during motor encoding (i.e.specific preparation, for example, preparing to speak a specific speech).The copy of detailed action codes selectively boosts the sensitivity of neural responses to the sensory target of actions (Fig. 1A, red arrow).B) The intact enhancement but possible deficits in inhibition functions in motor-to-sensory transformation in schizophrenia patients without auditory verbal hallucinations (non-AVHs).The negative symptoms of non-AVHs patients may cause weak motor intention that leads to diminished inhibitory function of CD at the beginning stage of an action (Fig. 1B, grey in the left part of the CD arrow), whereas the function of CD in the following motor processes (Fig. 1B, blue in the right part of the CD arrow, identical to that in Fig. 1A) as well as the specific modulation effects of enhancement in EC are preserved (Fig. 1B, red arrow, identical to that in Fig. 1A).C).The impaired inhibitory function of CD and imprecise enhancement function of EC in schizophrenia patients with auditory verbal hallucinations (AVHs).The malfunctioned monitoring of agency in AVHs is mediated by the impaired inhibitory function of CD throughout the course of motor processes (Fig. 1C, entire grey arrow).Moreover, the positive symptoms of AVHs --random perceptual-like experiences without corresponding acoustic stimulations -would be mediated by imprecise EC (Fig. 1C, hatched red arrow) that could activate multiple auditory neural representations around the sensory target of the action.That is, the positive symptoms of AVHs are an emergent property of the impaired sensorimotor systems in which a 'broken' CD misattributes the inducing sources of the auditory neural representations that are activated by a 'noisy' EC without external stimulations.(We are requiring permission for using Fig. 1A from the original publisher.)

Result Demographic and clinical data
Table S1 shows the participants' demographic data and the clinical variables.
One-way ANOVA analyses revealed a significant difference among three groups (AVHs, non-AVHs, and normal) in the GP task for age (F(2,56) = 8.06, p = 0.001), education (F(2,56) = 8.87, p < 0.001) and in the SP task for age (F(2,53) = 8.40, p = 0.001), education (F(2,53) = 4.64, p = 0.014).Fisher's LSD post hoc tests revealed no significant differences between AVHs and non-AVHs groups in education in GP and SP tasks (all p > 0.05).There was no significant difference in height, and weight among the three groups (all p > 0.05).The chi-square test showed no significant differences among the three groups in gender.Further, the positive symptom scores (t(1,38) = 2.75, p = 0.009 ) and P3 subscore (t(1,38) = 11.82,p < 0.001) were significantly higher in AVHs group than in non-AVHs group.The negative symptom scores and general psychopathology scores as well as PANSS total scores were not significantly different in AVHs and non-AVHs groups.Neither the age of onset nor the duration was significantly different between the two groups.
Further analysis revealed that the onset of articulation was consistently faster after preparation.Specifically, RTs of articulation were the fastest after SP (mean = 450.Illustration of a sample trial of general preparation (GP).After a fixation displayed for 500ms, a yellow visual cue of two symbols (#%) appeared in the center of the screen for a range of 1500ms to 2000ms with an increment of 100ms.Participants were asked to prepare to speak in the upcoming articulation task, although they did not know what to say because the symbols did not contain any linguistic information.In half of the trials, an auditory probe, either one of the four auditory syllables (/ba/, /pa/, /ga/, and /ka/) or a 1kHz pure tone, was played during the last 400ms of the preparatory stage.Another half of the trials did not include any auditory probes (GP NS ).After a blank screen with a range of 200ms to 400ms with an increment of 50ms, participants saw a green visual cue that was one of the four syllables (/ba/, /pa/, /ga/, and /ka/) in the center of the screen for a maximum of 1200ms and were asked to produce the syllable as fast and accurately as possible.B) Illustration of a sample trial of specific preparation (SP).The procedure was similar to the GP task with two exceptions: 1) the visual cue during the preparatory stage was a red syllable randomly selected from the four syllables (/ba/, /pa/, /ga/, and /ka/), and 2) an auditory probe was presented in every trial during the preparatory stage.The auditory probes were either the same as or different from the visual cue, yielding two conditionsauditory syllables were congruent (SPcon) or incongruent (SPinc) with the syllable that participants prepared to speak.C) & D) Behavioral results of AVHs and non-AVHs patients.The speed of articulation was measured as reaction time (RT).In both groups, the RTs in GP (with or without auditory probes) and SP were significantly faster than those in NP, suggesting that preparation was carried out in both groups and in all conditions.Error bars indicate ±SEM.* * P < 0.01, * * * P < 0.001.
In the non-AVHs group (Fig. 2D), the statistical results were similar to the ones in the AVHs group.A repeated-measure one-way ANOVA on RTs found a significant main effect of preparation (F(3,57) = 128.99,p < 0.01, partial η 2 = 0.59).Further analysis revealed that the onset of articulation was consistently faster after preparation.were not significantly different between GP and GP NS (t(19) = 1.99, p = 0.06, d = 0.15).These results suggested that participants performed the GP task according to the visual cues and CD was available in the general preparation stage.These consistent behavioral results confirmed that both groups of patients can perform the behavioral preparation tasks.

The impaired function of motor signals during general preparation
We first performed within-subject statistical analyses of paired t-tests on the ERPs to the auditory probes in GP to investigate the modulatory effects of CD signals on auditory processes in each patient group.In the AVHs group, the N1 and P2 topographies showed typical auditory response patterns in both GP and B conditions (Fig. 3A).However, the magnitude of neural responses in GP was not significantly different from B, neither in the early auditory responses of N1 component (t(19) = 2.39, p = 0.054, d = 0.47) nor in the later auditory responses of P2 component (t(19) = 0.97, p = 0.43, d = 0.10) (Fig. 3B).These results contrasted with the ones obtained in the normal population in which GP suppressed auditory responses (Fig. S1) [39].
These results supported the hypothesis that the function of CD was impaired in AVHs patients.Due to the costs and efforts to conduct a direct replication of the predicted and observed null results in the GP condition, we implement a bootstrapping procedure to estimate the reliability of the null results.The simulation results (Fig. S2) showed that the suppression (modulation index value less than 0) was outside the 99% confidence interval, suggesting that the observed null results in the AVH group were highly unlikely due to chance.
In the non-AVHs group, the results were similar to those in the AVHs group.The N1 and P2 topographies showed typical auditory response patterns in both conditions (Fig. 3C).The magnitude of neural responses in GP was not significantly different from B, neither in N1 (t(19) = 0.12, p = 0.91, d = 0.02) nor in P2 (t(19) = 1.96, p = 0.09, d = 0.34) (Fig. 3D).These results suggest that the effects of CD during the earliest stage of motor intention were also absent in non-AVHs patients.
To explore the modulation functions of CD signals on tones, we conducted paired t-tests on the auditory responses to tones between GP and B for N1 and P2 separately.

AVHs and non-AVHs
We next investigated the function of EC on the ERPs to the auditory probes in SP.In the AVHs group, the N1 and P2 topographies showed typical auditory response patterns among SPinc, SPcon and B conditions (Fig. 4A).The magnitude of N1 was larger than that in B when the auditory syllables were incongruent with the contents of SP visual cues (SPinc) (t(19) = 3.69, p = 0.004, d = 0.72).The effect was not significant in the later auditory responses of P2 (t(19) = 1.69, p = 0.43, d = 0.22).
However, when the auditory syllables were congruent with the specific preparation (SPcon), the effect was not significant in N1 (t(19) = 1.26, p = 0.30, d = 0.23 ), nor in P2 (t(19) = 1.52, p = 0.43, d = 0.20) (Fig. 4B).These results were opposite to the results in normal controls in which motor signals during SP enhanced the perceptual responses to the congruent auditory syllable probes (Fig. S4) [39].The observed modulation effects in AVHs suggested that EC was available during specific preparation, but the opposite modulation patterns (enhancement in SPinc in AVHs compared with enhancement in SPcon in normal) indicated a 'noisy' EC that yielded imprecise modulation on auditory responses during specific preparation in AVHs.In the non-AVHs group, the N1 and P2 topographies showed typical auditory response patterns in all conditions (Fig. 4C).When the auditory syllables were congruent with the specific preparation (SPcon), the response magnitude of the N1 component was larger than that in B (t(19) = 3.18, p = 0.01, d = 0.56), whereas the response magnitude of P2 component was reduced relative to B (t(19) = 3.07, p = 0.02, d = 0.62).In SPinc, the response magnitude of N1 (t(19) = 0.73, p = 0.64, d = 0.13) and P2 (t(19) = 1.91, p = 0.09, d = 0.44) was not significantly different from B (Fig. 4D).The results of SP in non-AVHs were consistent with the results from the normal control group (Fig. S4) [39], suggesting an intact EC function in non-AVHs.topographies showed typical auditory response patterns in both conditions and groups (Fig. S5 A&C).The lack of modulation on tones during specific preparation in both patient groups was consistent with the results in normal controls [39], indicating that EC contained the task-related information in both AVHs and non-AVHs.

The correlations between clinical symptoms and neural modulation effects
We further investigate the distinct impairment of motor-to-sensory transformation in schizophrenia by exploring the relation between the clinical symptoms and neural measures of modulation effects.According to our hypothesis that the CD function is impaired in the AVHs group, the natural derivation of the hypothesis is that the severity of the hallucination symptoms correlates with the degree of impairment in the CD inhibitory function.That is, in terms of neural measures, the severity of the symptoms would correlate with the measures of suppression in the GP condition.
Therefore, we carried out Pearson correlation analysis between the GP modulation index (calculated as GP minus B) and two positive symptom scores (PTotal: positive symptoms score; and AHRSTotal: auditory hallucination symptoms score).A significant positive correlation was observed between the PTotal and GP modulation index after multiple-comparison correction (Fig. 5A, r = 0.578, p = 0.008).These significant symptom-neural correlation results, complementing the predicted negative group level ERP results in the GP condition (Fig. 3), provide additional strong evidence supporting the 'broken CD' hypothesis in schizophrenia patients.
According to our hypothesis about EC, the positive symptoms of auditory hallucinations random perceptual-like experiences without corresponding acoustic stimulations -would be mediated by noisy EC that could activate neighboring auditory neural representations around the sensory target of the action.That is, the noisy EC modulates and enhances the sensitivity of neural responses to unprepared auditory units.To test this hypothesis, a difference score was first calculated by subtracting the N1 response amplitude in the B condition from the SPinc condition in the AVHs group.The difference score represents the magnitude of the N1 enhancement effects in the SPinc condition.The N1 enhancement magnitude significantly and positively correlated with the AHRS total scores (Fig. 5B, r = 0.562, p = 0.01 ).That is, the more severe the AVHS symptoms, the more enhancement in the N1 responses in the SPinc condition.These results suggest that the enhancement of N1 response magnitude to the unprepared syllables was related to the degree of AVHs symptom severity --noisy and imprecise EC in AVHs may relate to the various forms of auditory hallucinations.
We further explored the relations between neural measures of CD/EC and negative symptoms.Pearson correlation analyses did not reveal any significant correlation between negative symptom scores and CD/EC metrics in AVHs or non-AVHs groups.

Modeling results of dissociative impairment of CD and EC in AVHs and non-AVHs
To collaboratively simulate the dissociations of impairment between the effects of CD and EC in AVHs and non-AVHs groups, we quantified our hypotheses in a two-layer neural network model.The upper motor layer had two functional pathways that linked to the lower auditory layer: an indirect pathway via an interneuron to inhibit all nodes in the auditory layer, and a direct pathway for modulating the gain of corresponding auditory nodes (Fig. 6A).These indirect inhibitory and direct enhancement pathways manifest the functions of CD and EC, respectively.This bifurcation of motor signals successfully explained the distinct modulation directions in GP (Fig. 6B, left) and SP (Fig. 6C, left) in normal participants [39].simulating the enhancement function of EC during specific preparation).A trial that /da/ is prepared to speak is taken as an example, indicated by the only red in the motor 'da' neuron with a solid arrow pointing to the auditory 'da' neuron with a red circle.Other unprepared syllables do not activate the motor neurons and dashed arrows indicate no modulation on the corresponding auditory neurons.Compared with the normal population (left plot), for non-AVHs (middle plot), the weaker CD function is modeled as the reduced inhibition strength of the interneuron (indicated by a lightened red cross over the interneuron, with dashed blue lines representing reduced inhibition in downstream).Whereas the modulation strength of the EC enhancement function is preserved in non-AVHs, indicated by the same activation in the motor layer and modulation patterns to auditory neurons as the normal population (left).For AVHs (right plot), the inhibitory function of CD could be even more impaired (a red cross over the interneuron) and the enhancement function of EC is imprecise as its modulation not only on the target unit of 'da' but also over all neighboring units (red in all motor units and solid arrows to all auditory units).For the non-AVHs group, we set the inhibition strength of the interneuron as a free parameter, while other parameters remained the same as the previous study of fitting the results of the normal population.If only CD at the movement intention stage was impaired but EC at the specific preparation stage was intact in the non-AVHs group, the inhibition strength of the interneuron would be significantly smaller than that of the normal population, whereas the same gain modulation in the direct pathway that used in fitting normal population would be able to fit the results of non-AVHs (Fig. 6A, middle).More importantly, we hypothesized a 'broken' CD and a 'noisy' EC for the AVHs group.The 'broken' CD hypothesis led to a similar prediction that the inhibitory strength of the interneuron would be smaller than the normal population, and even smaller than non-AVHs (Fig. 6A, right).To test the hypothesis of 'noisy' EC, we manipulated the ratio of the gain modulation strength between the prepared and unprepared syllables.The 'noisy' EC hypothesis derived a prediction that the best-fitted parameter for the SP results in AVHs would yield relatively more gain over the neighboring auditory nodes than that of the prepared auditory target (Fig. 6A, right).
For the non-AVHs group, the simulation results revealed that, during GP, the inhibitory effect was dampened because of deficits in the interneuron.The best-fitted parameter of inhibitory strength was 0.2440, compared with a stronger inhibition of 0.4372 in the normal population.The weaker inhibitory strength made the inhibition of GP disappear (Fig. 6B, middle).After temporal averaging of the peak component in the waveform responses, the simulation result of suppression in GP relative to B was consistent with the empirical observations in the GP condition for non-AVHs group (Fig. 6D).The Bayes factor of comparison between the simulation results and empirical results in GP condition favored the null (scaled JZS Bayes factor = 4.30), suggesting the model captured the absence of suppressed auditory responses in the GP for non-AVHs group.
For the AVHs group, a similar inhibitory deficit was built in the interneuron (Fig. 6A.right).The simulation results suggest that during GP, the inhibitory strength was decreased to 0.0695, much smaller than that of the normal population (0.4372), and smaller than that of the non-AVHs group (0.2440).The much weaker inhibitory strength yielded the absence of inhibition in GP (Fig. 6B, right).The difference between temporal averages of the simulated peak components of GP and B in the AVHs group was not different from the empirical results, supported by the Bayes factor (scaled JZS Bayes factor = 4.30), suggesting the model also captured the absence of suppression in the GP for AVH group.
The modulation effects diverged between AVHs and non-AVHs groups in SP --the non-AVHs group had similar effects as the normal population, whereas AVHs had an opposite modulation pattern (empirical results in Fig. 4).This was hypothesized as the EC function differences -'noisy' in AVHs group, whereas the EC function remained as precise in the non-AVHs group as normal group.For the simulation of SP results in non-AVHs, the gain modulation function remained the same as that in the normal population, indicated by a similar activity pattern of motor units and of modulation arrows to auditory units between non-AVHs (Fig. 6A, middle) and normal (Fig. 6A, left).The simulation results showed the enhancement effects in SP compared to B in the non-AVHs group (Fig. 6C, middle).The temporal averages around the peak of simulated waveform responses were not statistically different from the empirical data, supported by the Bayes factor (scaled JZS Bayes factor = 4.00 for SPcon, and 3.57 for SPinc), suggesting the intact modulation of EC in non-AVHs.Interestingly, the simulation results of SP in non-AVHs must use the normal inhibitory strength of the interneuron rather than the simulated decreased inhibitory strength obtained in GP of non-AVHs, and reduce the auditory input connection strength to adjacent auditory nodes by about 30 percent.This indicated that the inhibitory function may vary across the preparation stages that potentially originated from different hierarchies of the neural pathway for actions [39] and the deficits of CD in the non-AVHs group may be only in the early intentional stage but not in later preparatory stages.
For the AVHs group, in addition to the inhibitory deficits in the interneuron, the gain modulation function was hypothesized to be 'noisy'.The 'noisy' gain modulation was modeled as a parameter of the ratio between the modulation gain on prepared and unprepared auditory nodes.That is, the gain modulation in AVHs may not be as precise as that in normal or non-AVHs groups (indicated in Fig. 6A right plot, the motor units for the unprepared syllables were also red and the downstream modulations were all solid arrows in AVHs, compared to the inactivated motor units and dashed downstream modulation arrows for the unprepared syllables in the normal and non-AVHs group in Fig. 6A left and middle).The simulation was performed simultaneously for the SPcon and SPinc results in AVHs.The best-fitted parameter of the ratio was 2.848, yielding the modulation gain between prepared and unprepared nodes of 0.351: 2.848, compared with that in normal and non-AVHs groups of 1.919: 1.This more 'spread-out' modulatory gain to the neighboring nodes of the prepared target resulted in smaller responses to SPcon but stronger responses to SPinc as compared to B (Fig. 6C).The temporal averages around the peak of simulated waveform responses were statistically not different from the empirical data, as supported by the Bayes factor (scaled JZS Bayes factor = 4.27 for SPcon, and 4.30 for SPinc), suggesting the imprecise modulation by a 'noisy' EC in AVHs.

Discussion
We investigated the modulation functions of motor signals on auditory processing at distinct stages of speech preparation in schizophrenia patients.Our behavioral, electrophysiological, and modeling results collaboratively demonstrated distinct impairments in the motor-to-sensory transformation between subgroups of clinical populations.The symptoms of AVHs are mediated by the impaired source monitoring function of CD that results in the absence of inhibition of auditory responses in the general speech preparation, as well as the imprecise activation function of EC that results in the varied enhancement and sensitization of auditory cortex during specific speech preparation.These results suggest that 'broken' CD plus 'noisy' EC causes erroneous monitoring of the imprecise generation of internal auditory representation and hence yields AVHs.
The absence of suppression effects during general preparation in schizophrenia patients is the negative evidence supporting that CD signals can be generated during the movement intention stage even without any preparatory contents.Compared with the function of ubiquitously suppressing neural responses to speech in normal controls [39,40], the CD did not function in both groups of schizophrenia patients with and without AVHs at the earliest stage of motor intention (Fig. 3).These results were consistent with immense literature about the weaker or absent action-induced sensory suppression in schizophrenia [11,27,[41][42][43], as well as findings that schizophrenia patients elicit a smaller readiness potential before movement [44] than normal controls [41,45].Our results delineate the temporal dynamics of the impaired function of CD that can occur in the earliest stage of motor intention, complementing with and extending from most findings during the action execution.
Different causes may mediate the absence of inhibition effects during general preparation in distinct clinical subgroups.Lack of desire to act may be a common cause in both patient groups that decreases the inhibitory strength of CD on auditory processes (Fig. 3) because no significant differences were found in the severity of their negative symptoms.The ubiquitous pathophysiological negative symptoms in schizophrenia may generate weaker CD in the motor intention stage in both patient groups.That is, the lack of inhibitory effects during general action preparation may be a biomarker for less intention and negative symptoms.However, impaired CD functions in motor-to-sensory transformation may be a cause that is unique in AVHs in addition to the deficits in the generation of CD due to negative symptoms.
Although as predicted, no difference in the negative empirical results of modulation by general preparation (Fig. 3), the symptom-neural correlation revealed a significant correlation between the severity of positive symptoms and impairment of CD inhibitory function in AVHs group, providing strong evidence at the individual level supporting the hypothesis (Fig. 5A).Moreover, computational model results (Fig. 6) reveal 1) a greater degree of impairment in the inhibition strength of the interneuron in AVHs compared with non-AVHs; and 2) the impaired function of CD continued throughout the specific speech preparation stage in AVHs, whereas the empirical results of modulation in SP in non-AVHs require the intact CD inhibitory strength to fit.All these pieces of evidence regarding the degree and temporal extent of the inhibitory function deficits suggest the impairment of CD in the motor-to-sensory transformation in AVHs.Our results of more severe impairment of CD in general preparation and throughout specific preparation in AVHs but not in non-AVHs are consistent with the findings that transcranial magnetic stimulation affected the sense of agency only when stimulation time locked in action planning, rather than in the physical consequences of the actions appeared [46].The empirical and modeling results consistently support that the impairment of CD function is associated with an abnormal sense of agency in AVHs patients [28].
The EC function and its impairment also show dissociation between AVHs and non-AVHs.In non-AVHs patients, the EC function is the same as normal --the motor signals in specific preparation enhanced the neural responses only to the prepared syllable (Fig. 4).However, in AVHs patients, the motor signals in specific preparation enhanced the neural responses to the unprepared syllable (Fig. 4).And the modulation effects of enhancement are positively correlated with the severity of AVH symptoms (Fig. 5B).Modeling results further quantified that the different modulation patterns between AVHs and non-AVHs were caused by the imprecise modulation from the motor to sensory units that provide incorrect gains over the non-target of the specific preparation (Fig. 6).These results suggest that EC can be generated in the motor-to-sensory transformation pathway during specific preparation in AVHs patients.However, the EC is 'noisy' either in the generation process in the motor system or it is imprecisely mapped onto the auditory system.As a result, the 'noisy' EC modulates and enhances the sensitivity of neural responses to unprepared auditory units.The empirical ERP modulation effects, correlation results with AVH symptoms and model simulation results collaboratively support the hypothesis of 'noisy' EC in AVHs.This imprecise EC in AVHs may relate to the 'non-sense' and various forms of auditory hallucinations.
In previous studies, action-induced suppression [21,22,47,48] and enhancement [30][31][32][33][34] have been observed in the normal population and animal models.By considering the different characteristics of motor signals across temporal dynamics of motor processes, it has been proposed that the copy of motor signals at different action stages may distinguish into CD and EC that mediate distinct functions for regulating actions [39].In this study, we found distinct impairments in AVHs between general and specific preparation stages (Figs.3&4).The observed distinct impairments in different speech preparation stages offer evidence from a clinical perspective that is consistent with empirical neuroscience results in the normal population and supports the updated theoretical framework of internal forward models [39].
The observed double dissociations of CD and EC functions between AVHs and non-AVHs reveal the impairments in the motor-to-sensory transformation that mediate the positive symptoms of auditory hallucinations.The positive nature of auditory hallucinations requires the active construction of neural representations that mediate perceptual-like experience.Our observation of 'noisy' EC that imprecisely sensitizes auditory cortices provides a foundation for inducing subjective experience without external stimulation.Together with the impairment in CD that leads to less suppression and hence deficits in labeling the sources that induce neural responses, hallucinations about experiencing perceptual events would occur.That is, the combination of impairments on distinct functions between motor and sensory systems mediate the positive symptoms of auditory hallucination, which is consistent with the hypothesis of motor-to-sensory transformation as an origin of hallucinations [16,27,[49][50][51] -the impaired monitoring function misattributes the sources of internally motor-induced [8] or other top-down induced neural representations [52,53].The conceptual, anatomical, and functional distinct motor signals of CD and EC, instead of sole inhibitory function in the motor-to-sensory transformation, collaboratively contribute to the positive symptoms of auditory hallucinations.
Most previous studies have explored the differences in impaired motor-to-sensory transformation signals between schizophrenia patients and normal controls [28,[54][55][56].In this study, we explored how the motor signals regulated perceptual neural responses between subgroups of schizophrenia patients with different symptoms.This hypothesis-driven symptom-based approach yields novel insights into the potential neural mechanisms that mediate different aspects of deficits in schizophrenia.By distinguishing the uniqueness of psychotic symptoms in the same categorized mental disorder, the distinct impairments in the motor-to-sensory transformation have been revealed, which delineates the potential deficits mediating positive symptoms in mental disorders.Moreover, considering the overlapping symptoms between subgroups of patients can provide insights into possible causes, for example, the negative symptoms in both AVHs and non-AVHs may reveal the deficits in the motor system in relation to anhedonia and amotivational syndrome.The approach of comparing unique and common symptoms may expand over different types of mental disorders, such as auditory hallucinations in schizophrenia and bipolar disorder to investigate the potential common causes from a cognitive neuroscience perspective.
Adding the neural bases of symptoms across different types of mental disorders complements the symptoms-based categorization and may provide a 2-D matrix for a more precise diagnosis of mental disorders [57].
Our study highlights cognitive computation as a crucial interface to bridge neural circuits to mind and behavior, especially in understanding mental disorders.Recently, computational psychiatry has emerged as a novel quantitative cognitive account for probing the mechanisms that mediate mental disorders [58][59][60][61].In this study, we utilized a computational modeling approach and identified the subtle differences in the negative results during general preparation between AVHs and non-AVHs.
Moreover, the computational modeling enables us to differentiate the distinct impairments of CD and EC throughout the evaluation of actions -parametric simulation using hypothesized intact and impaired values overcome the temporal overlaps of CD and EC in the specific preparation that would be hard, if not impossible to investigate using behavioral or non-invasive cognitive neuroscience approaches on human participants with mental disorders.The consistent EEG and modeling results mechanistically reveal the predictive functions of motor and sensory networks that may mediate the symptoms of psychosis [16,38].Our endeavors of combining behavior, electrophysiology, and modeling manifest Marr's computational approach [62] and provide a possible link between mental and behavioral status with neural circuits [63,64].The computational approach puts the cognition back to the investigation of mental disorders [65], and yields testable hypotheses at the cognitive, system and even cellular and molecular levels to collaboratively understand mental disorders.
Our neural network model aligns with previous Bayesian inference models that explain the positive symptoms of schizophrenia.False prediction errors have been assumed as the cause of the positive symptoms [38,66,67].The inaccurate prior expectancies distort the integration with the sensory evidence, and the resultant false prediction errors create disturbance in inference updating.Specific to hallucinations, recent models propose that abnormally strong priors dominate and overwrite prediction errors so that both contents and the presence of auditory hallucinations can be explained [68].Our model, based on two distinct modulatory functions in the motor-to-sensory transformation, assumes two types of predictions that can presumably integrate both inference models.EC serves as a content prediction, resembling the strong priors that would elicit the specific auditory neural representation without corresponding external stimulation [4,8,35,36].Whereas, CD serves as a prediction for agency, and the impairment would cause the failure to explain away the internally generated auditory neural representations that are evoked by EC [49,52,69,70].Moreover, our neural network model provides a mechanistic account and potentially ground the psychological constructs of inference and prediction in the motor and sensory systems.The hypothesized origins of auditory hallucinations at the level of neural representation and computation can inspire future neuroscience studies at the cellular, system, and cognitive levels.
By probing the impairments in the interactive neural processes between motor and sensory systems, we observed the functional distinctions between CD and EC, and their impairments in relation to auditory hallucinations in schizophrenia.The pathophysiology of schizophrenia involves a ubiquitously distributed motor-sensory circuitry in which the 'broken' CD dysfunctionally misattributes the sources of the neural activity induced by 'noisy' EC -the failure of dampening the internally induced sensory neural activity leads to hallucinatory experiences.Distinct impairments in functional granularity of motor-to-sensory transformation mediate positivity symptoms of agency deficits in mental disorders.

Figure 1 .
Figure 1.Schematics of distinct functions of motor signals in motor-to-sensory transformation across temporal stages of action in normal and clinical populations.A) The distinct inhibition and enhancement functions in motor-to-sensory transformation in the normal population.Corollary discharge (CD) is a general discharge signal from the motor system that does not necessarily include any content information.CD is available at all stages of motor processes and can onset as early as in

Figure 3 .
Figure 3.The absence of modulation effects on auditory responses during general preparation (GP) in both AVHs and non-AVHs groups.(A) ERP time course and topographic responses for GP and B conditions in AVHs patients.Peak amplitudes and latencies of the N1 and P2 components were observed in the GFP waveform for each condition.The response topographies at each peak latency are shown in boxes with the same color-code of each condition.(B) Mean GFP amplitudes at N1 and P2 latencies in GP (blue) and B (gray) conditions in AVHs patients.(C) ERP time course and topographic responses in GP and B conditions in non-AVHs patients.(D) Mean GFP amplitudes at the N1 and P2 latencies in GP (blue) and B (gray) conditions in non-AVHs patients.No significant differences between GP and B were observed in either group.Error bars indicate ± SEMs.

Figure 4 .
Figure 4.The opposite modulation effects on auditory responses during specific preparation (SP) between AVHs and non-AVHs groups.(A) ERP time course and topographic responses for SP and B conditions in AVHs patients.Typical N1 and P2 auditory response components were observed in GFP waveforms of each condition.The response topographies at each peak latency are shown in boxes with the same color-code of each condition.(B) Mean GFP amplitude at N1 and P2 latencies for SP (red) and B (gray) conditions in AVHs patients.Responses in SPinc were significantly larger than those in B in N1 component.(C) ERP time course and topographic responses for SP and B conditions in non-AVHs patients.(D) Mean GFP amplitudes at N1 and P2 latencies for SP and B conditions.Responses in SPcon were significantly larger than those in B in N1 components, contrasting with the results in AVHs in B).Error bars indicate ±SEMs.* for p < 0.05, * * for p < 0.01, FDR-corrected for multiple comparisons.

Figure 5 .
Figure 5. Correlation between positive symptoms and neural measures.A) The correlation between positive symptom total scores and GP modulation index in AVHs group.B) The correlation between AHRS total scores and SPinc modulation index in AVHs group.PTotal represents the positive symptom total scores in PANSS (Positive and Negative Syndrome Scale); AHRS (Auditory Hallucinations Rating Scale) total scores represent the severity of auditory hallucinations symptoms; GP modulation index represents the magnitude of the N1 suppression effects in the GP condition; SPinc modulation index represents the magnitude of the N1 enhancement effects in the SPinc condition.

Figure 6 .
Figure 6.Model simulation results of distinct impairments of CD and EC in clinical populations.A) model architecture and manipulations that quantify the hypothesized neural impairments mediating AVH.Speech units in the motor layer (upper) link to the units in the auditory layer (lower) via two pathways.An interneuron receives signals from each unit in the motor layer and inhibits all units in the auditory layer (blue, simulating the inhibitory function of CD during general preparation).Moreover, signals from each motor unit bifurcate and sensitize its corresponding auditory unit (red arrows, The simulation results of time course responses in B) GP and in C) SP conditions for normal (left), non-AVHs (middle), and AVHs (right) groups.Each line represents the simulated dynamics of responses from the corresponding auditory units, with black line for B condition, blue line for GP condition; solid and dashed red lines for SPcon and SPinc, respectively.The simulation results of component response magnitude compared with the empirical data in D) GP, E) SPcon, and F) SPinc conditions.The bars represent the observed modulation effects of speech preparation on N1 auditory responses.The stars on the bars represent the simulation results in a given condition and group.Both empirical and simulation results are normalized by baseline conditions.The model simulations capture the absence of inhibition during GP as well as the opposite modulation patterns in SP among different groups.